The long-term goals of this research program are to increase our basic knowledge of how plasma proteins interact with circulating blood platelets leading to their activation and shape change at the site of vascular injury. These reactions play a significant role in cardiovascular disease leading to heart attack and stroke in humans. The approach includes an investigation of the signaling process initiated on the surface of the platelet by thrombin and von Willebrand factor (VWF) and their relationship to the proteins of the cytoskeleton that control the shape of the platelets. These studies will focus on the glycoprotein Ib-lX-V complex, its binding to the a, b, and g filamins in the platelets, and the relationship of the filamins to a guanine nucleotide exchange factor (GEF) with DH-PH domains. This GEF called filamin associated protein has been characterized in our laboratory. These studies will then be extended to the specific small GTPases such as Rho, Rac, and Cdc42 that function as substrates for the GEFs and play a specific role in the development of filopodia, lamellipodia, stress fibers and focal adhesions when platelets are activated. In parallel experiments, the protease-activated receptors (PAR1 and PAR4) will be further examined for their role in platelet shape change via the small GTPases (Rho, Rac, Cdc42) and the platelet GEFs.